Dengue virus (DENV) causes dengue fever (DF) and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS), the most prevalent mosquito-borne viral illnesses in humans worldwide. Studies suggest that sub-neutralizing concentrations of DENV-specific antibodies may contribute to viral replication and disease severity during secondary DENV infections via a phenomenon known as "antibody-dependent-enhancement (ADE)." However, due to the lack of an adequate animal model, the cellular and molecular bases of ADE- induced dengue disease are poorly understood, and the safety of DENV vaccine candidates cannot be fully evaluated. We have recently developed a mouse model of ADE-induced DENV disease, thereby allowing us to develop and evaluate the safety and efficacy of new DENV vaccines that are likely to prevent ADE. Herein, we propose to develop a novel DENV-specific mucosal vaccine candidate that targets M cells and test the hypothesis that mucosal immunization prevents ADE-induced severe DENV disease and affords better protection against DENV infections than subcutaneous immunization. The two specific aims are as follows. First, we will determine whether mucosal vaccination protects against homologous or heterologous DENV infection (Aim 1). Second, we will examine whether mucosal vaccination prevents ADE of DENV infection and disease (Aim 2). Completion of these studies should elucidate the feature of the anti-DENV antibody response that results in protection versus ADE and lead to the development a novel, effective vaccine that is easier to administer than conventional parenteral vaccines.